Dual effect of tamoxifen, an anti-breast-cancer drug, on intracellular Ca2+ and cytotoxicity in intact cells

Chung Ren Jan*, Jin Shiung Cheng, Kang Ju Chou, Shiou Ping Wang, Kam Chung Lee, Kwong Yui Tang, Li Ling Tseng, Hung Ting Chiang

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

15 Scopus citations


The effect of tamoxifen on Ca2+ signaling and viability in Madin Darby canine kidney (MDCK) cells was investigated by using fura-2 as a Ca2+ probe. Tamoxifen evoked a rise in cytosolic free Ca2+ levels ([Ca2+](i)) concentration-dependently between 1 and 50 μM with an ECS0 of 10 μM. The response was decreased by extracellular Ca2+ removal. In Ca2+-free medium, pretreatment with 5 μM tamoxifen abolished the [Ca2+](i) increase induced by the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin (1 μM), but pretreatment with brefeldin A (50 μM; a Ca2+ mobilizer of the Golgi complex), thapsigargin (an inhibitor of the endoplasmic reticulum Ca2+ pump), and carbonylcyanide m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler), only partly inhibited tamoxifen-induced [Ca2+](i) increases. This suggests that tamoxifen released Ca2+ from multiple pools. Addition of 3 mM Ca2+ induced a [Ca2+](i) rise after pretreatment with 5 μM tamoxifen in Ca2+-free medium. Inhibiting inositol 1,4,5-trisphosphate formation with the phospholipase C inhibitor U73122 (2 μM) did not alter 5 μM tamoxifen-induced Ca2+ release. The [Ca2+](i) increase induced by 5 μM tamoxifen was not altered by La3+, nifedipine, verapamil, or diltiazem. Tamoxifen (1-10 μM) decreased cell viability in a concentration- and time-dependent manner. Tamoxifen (5 μM) also increased [Ca2+](i) in neutrophils, bladder cancer cells, and prostate cancer cells from humans and glioma cells from rats. Collectively, it was found that tamoxifen increased [Ca2+](i) in MDCK cells by releasing Ca2+ from multiple Ca2+ stores in a manner independent of the production of inositol 1,4,5-trisphosphate and also by triggering Ca2+ influx from extracellular space. The [Ca2+](i) increase was accompanied by cytotoxicity. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)58-63
Number of pages6
JournalToxicology and Applied Pharmacology
Issue number1
StatePublished - 01 10 2000
Externally publishedYes


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